Nicola L.M. Paul

Genetic Heritability of Ischemic Stroke and the Contribution of Previously Reported Candidate Gene and Genomewide Associations

Background and Purpose— The contribution of genetics to stroke risk, and whether this differs for different stroke subtypes, remains uncertain. Genomewide complex trait analysis allows heritability to be assessed from genomewide association study (GWAS) data. Previous candidate gene studies have identified many associations with stoke but whether these are important requires replication in large independent data sets. GWAS data sets provide a powerful resource to perform replication studies. Methods— We applied genomewide complex trait analysis to a GWAS data set of 3752 ischemic strokes and 5972 controls and determined heritability for all ischemic stroke and the most common subtypes: large-vessel disease, small-vessel disease, and cardioembolic stroke. By systematic review we identified previous candidate gene and GWAS associations with stroke and previous GWAS associations with related cardiovascular phenotypes (myocardial infarction, atrial fibrillation, and carotid intima-media thickness). Fifty associations were identified. Results— For all ischemic stroke, heritability was 37.9%. Heritability varied markedly by stroke subtype being 40.3% for large-vessel disease and 32.6% for cardioembolic but lower for small-vessel disease (16.1%). No previously reported candidate gene was significant after rigorous correction for multiple testing. In contrast, 3 loci from related cardiovascular GWAS studies were significant: PHACTR1 in large-vessel disease (P=2.63e−6), PITX2 in cardioembolic stroke (P=4.78e−8), and ZFHX3 in cardioembolic stroke (P=5.50e−7). Conclusions— There is substantial heritability for ischemic stroke, but this varies for different stroke subtypes. Previous candidate gene associations contribute little to this heritability, but GWAS studies in related cardiovascular phenotypes are identifying robust associations. The heritability data, and data from GWAS, suggest detecting additional associations will depend on careful stroke subtyping.

Transient isolated brainstem symptoms preceding posterior circulation stroke: a population-based study

Summary Background Transient isolated brainstem symptoms (eg, isolated vertigo, dysarthria, diplopia) are not consistently classified as transient ischaemic attacks (TIAs) and data for prognosis are limited. If some of these transient neurological attacks (TNAs) are due to vertebrobasilar ischaemia, then they should be common during the days and weeks preceding posterior circulation strokes. We aimed to assess the frequency of TNAs before vertebrobasilar ischaemic stroke. Methods We studied all potential ischaemic events during the 90 days preceding an ischaemic stroke in patients ascertained within a prospective, population-based incidence study in Oxfordshire, UK (Oxford Vascular Study; 2002–2010) and compared rates of TNA preceding vertebrobasilar stroke versus carotid stroke. We classified the brainstem symptoms isolated vertigo, vertigo with non-focal symptoms, isolated double vision, transient generalised weakness, and binocular visual disturbance as TNAs in the vertebrobasilar territory; atypical amaurosis fugax and limb-shaking as TNAs in the carotid territory; and isolated slurred speech, migraine variants, transient confusion, and hemisensory tingling symptoms as TNAs in uncertain territory. Findings Of the 1141 patients with ischaemic stroke, vascular territory was categorisable in 1034 (91%) cases, with 275 vertebrobasilar strokes and 759 carotid strokes. Isolated brainstem TNAs were more frequent before a vertebrobasilar stroke (45 of 275 events) than before a carotid stroke (10 of 759; OR 14·7, 95% CI 7·3–29·5, p<0·0001), particularly during the preceding 2 days (22 of 252 before a vertebrobasilar stroke vs two of 751 before a carotid stroke, OR 35·8, 8·4–153·5, p<0·0001). Of all 59 TNAs preceding (median 4 days, IQR 1–30) vertebrobasilar stroke, only five (8%) fulfilled the National Institute of Neurological Disorders and Stroke (NINDS) criteria for TIA. The other 54 cases were isolated vertigo (n=23), non-NINDS binocular visual disturbance (n=9), vertigo with other non-focal symptoms (n=10), isolated slurred speech, hemisensory tingling, or diplopia (n=8), and non-focal events (n=4). Only 10 (22%) of the 45 patients with isolated brainstem TNAs sought medical attention before the stroke and a vascular cause was suspected by their physician in only one of these cases. Interpretation In patients with definite vertebrobasilar stroke, preceding transient isolated brainstem symptoms are common, but most symptoms do not satisfy traditional definitions of TIA. More studies of the prognosis of transient isolated brainstem symptoms are required. Funding Wellcome Trust, UK Medical Research Council, Dunhill Medical Trust, Stroke Association, National Institute for Health Research (NIHR), Thames Valley Primary Care Research Partnership, and the NIHR Biomedical Research Centre, Oxford.

Sustained impact of UK FAST-test public education on response to stroke: a population-based time-series study.

Background Urgent assessment is essential after stroke. Several countries have had public education campaigns, based on the FAST (Face-Arm-Speech-Time) test to reduce delays in seeking attention. However, the impact of these campaigns on patient behavior is uncertain. Methods We prospectively determined patient behavior after incident major stroke (NIHSS > 3) in a UK population based study (Oxford Vascular Study) before (2002–2008) and after (2009–2013) introduction of the FAST TV-campaign and assessed any sustained impact of campaign continuation. Results Among 668 consecutive patients with major stroke, medical attention was sought by a bystander in 553 (89·6%). Patients were more likely to present directly to emergency services (OR = 2·18, 95%CI:1·54–3·09, P < 0·0001) after the campaign and to arrive at hospital within 3 h (OR = 2·18, 1·55–3·06, P < 0·0001). Median [IQR] time to seeking attention fell from 53 [15–265] to 31 [7–120] minutes (P = 0·005) and median time to hospital arrival from 185 [88–885] to 119 [78–256] minutes (P < 0·0001). On time-series analysis improvements in hospital arrival within 3 h and use of emergency medical services were significantly associated to initiation of the campaign (aOR = 3·11, 1·53–6·29, P = 0·002; and 2·22, 1·05–4·67, P = 0·036, respectively), independent of trend, age, sex, ethnicity, educational level, social class, prior stroke and stroke severity, and have been sustained to 2013. Conclusion Delays to seeking and receiving medical attention after major stroke in the UK. fell strikingly in 2009, coinciding with the start of the FAST TV campaign. That medical attention was sought by a bystander in nearly 90% of cases illustrates the importance of mass-media public education rather than focused programs in high-risk groups for major stroke.

Age- and sex-specific rates of leukoaraiosis in TIA and stroke patients: population-based study.

Objective: To determine any sex differences in age-specific prevalence or severity of leukoaraiosis, a marker of white matter ischemia, in population-based and clinic cohorts of TIA/stroke and in a systematic review of the literature. Methods: Age-specific sex differences were calculated for both CT and MRI in the Oxford Vascular Study (OXVASC) and in an MRI-based clinic cohort. We pooled odds ratios (ORs) for leukoaraiosis in women vs men from published studies by fixed-effect meta-analysis, stratified by patient characteristics (stroke vs nonstroke) and CT vs MRI. Results: Among 10 stroke studies (all CT-based), leukoaraiosis was most frequent in women (OR = 1.42, 95% confidence interval [CI] 1.27–1.57, p < 0.0001), with little heterogeneity between studies (p = 0.28). However, no such excess was seen in 10 reports of nonstroke cohorts (0.91, 0.67–1.24, p = 0.56). Moreover, excess leukoaraiosis in women on CT-imaging in OXVASC (1.38, 1.15–1.67, p = 0.001) was explained by their older age (age-adjusted OR = 1.01, 0.82–1.25, p = 0.90). Leukoaraiosis was more severe in older (≥75) women (CT-1.50, 1.14–1.97, p = 0.004 in OXVASC; MRI-1.70, 1.17–2.48, p = 0.006 in OXVASC and clinic cohort). However, leukoaraiosis was independently associated with early mortality (hazard ratio = 1.46, 1.23–1.73, p < 0.0001), suggesting that comparisons in older age groups will be biased by prior premature death of men with leukoaraiosis. Sex differences in severity of leukoaraiosis were not addressed in previous studies. Conclusions: Previously reported excess leukoaraiosis in women with TIA/stroke is likely to be confounded by age and apparently greater severity in older women is likely to be biased by premature death in men with leukoaraiosis.

Population-based study of capsular warning syndrome and prognosis after early recurrent TIA

Objective: Many guidelines recommend emergency assessment for patients with ≥2 TIAs within 7 days, perhaps in recognition of the capsular warning syndrome. However, it is unclear whether all patients with multiple TIAs are at high early risk of stroke and whether treatable underlying pathologies are more prevalent in this group. Methods: We studied clinical characteristics, Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and risk of stroke in 1,000 consecutive patients with incident and recurrent TIAs in a prospective, population-based study (Oxford Vascular Study). Results: Of 1,000 patients with TIAs, 170 had a further TIA within 7 days (105 within 24 hours). Multiple TIAs were not associated with carotid stenosis or atrial fibrillation, and much of the 10.6 (95% confidence interval [CI] 6.5−15.9) risk of stroke during the 7 days after the first TIA was due to patients with small-vessel disease (SVD) etiology (10 of 24 vs 8 of 146, odds ratio [OR] = 12.3, 95% CI 3.7–41.9, p < 0.0001), particularly those with motor weakness (i.e., capsular warning syndrome) compared with hemisensory events (9 of 15 [60%], 95% CI 35.3–84.7 vs 1 of 9 [11.1%], 95% CI 0–31.7, p = 0.03). The 7-day risk of stroke after a recurrent TIA was similar to the risk after a single TIA in patients with non-SVD TIA (8 of 146 [5.5%] vs 76 of 830 [9.2%], OR = 0.58, 95% CI 0.25–1.3, p = 0.20). Of the 9 patients with stroke after a capsular warning syndrome, all had the recurrent TIA within 24 hours after the first TIA, and the subsequent stroke occurred within 72 hours of the second TIA in 8. The ABCD2 scores of all preceding TIAs were ≥4 in all 9 patients with capsular warning syndrome before stroke. Conclusions: Capsular warning syndrome is rare (1.5% of TIA presentations) but has a poor prognosis (7-day stroke risk of 60%). Otherwise, recurrent TIA within 7 days is not associated with a greater stroke risk than that after a single TIA.

Age-Specific Incidence, Outcome, Cost, and Projected Future Burden of Atrial Fibrillation–Related Embolic Vascular Events

Background— Prevalence of atrial fibrillation (AF) is >10% at age ≥80 years, but the impact of population aging on rates of AF-related ischemic events is uncertain. Methods and Results— We studied age-specific incidence, outcome, and cost of all AF-related incident strokes and systemic emboli from 2002 to 2012 in the Oxford Vascular Study (OXVASC). We determined time trends in incidence of AF-related stroke in comparison with a sister study in 1981 to 1986, extrapolated numbers to the UK population and projected future numbers. Of 3096 acute cerebral or peripheral vascular events in the 92 728 study population, 383 incident ischemic strokes and 71 systemic emboli were related to AF, of which 272 (59.9%) occurred at ≥80 years. Of 597 fatal or disabling incident ischemic strokes, 262 (43.9%) were AF-related. Numbers of AF-related ischemic strokes at age ≥80 years increased nearly 3-fold from 1981–1986 to 2002–2012 (extrapolated to the United Kingdom: 6621 to 18 176 per year), due partly to increased age-specific incidence (relative rate 1.52, 95% confidence interval 1.31-1.77, P=0.001), with potentially preventable AF-related events at age ≥80 years costing the United Kingdom £374 million per year. At current incidence rates, numbers of AF-related embolic events at age ≥80 years will treble again by 2050 (72 974/year), with 83.5% of all events occurring in this age group. Conclusions— Numbers of AF-related incident ischemic strokes at age ≥80 years have trebled over the last 25 years, despite the introduction of anticoagulants, and are projected to treble again by 2050, along with the numbers of systemic emboli. Improved prevention in older people with AF should be a major public health priority.

Feasibility, safety and cost of outpatient management of acute minor ischaemic stroke: a population-based study

Background Outpatient management safely and effectively prevents early recurrent stroke after transient ischaemic attack (TIA), but this approach may not be safe in patients with acute minor stroke. Objective To study outcomes of clinic and hospital-referred patients with TIA or minor stroke (National Institute of Health Stroke Scale score ≤3) in a prospective, population-based study (Oxford Vascular Study). Results Of 845 patients with TIA/stroke, 587 (69%) were referred directly to outpatient clinics and 258 (31%) directly to inpatient services. Of the 250 clinic-referred minor strokes (mean age 72.7 years), 237 (95%) were investigated, treated and discharged on the same day, of whom 16 (6.8%) were subsequently admitted to hospital within 30 days for recurrent stroke (n=6), sepsis (n=3), falls (n=3), bleeding (n=2), angina (n=1) and nursing care (n=1). The 150 patients (mean age 74.8 years) with minor stroke referred directly to hospital (median length-of-stay 9 days) had a similar 30-day readmission rate (9/150; 6.3%; p=0.83) after initial discharge and a similar 30-day risk of recurrent stroke (9/237 in clinic patients vs 8/150, OR=0.70, 0.27–1.80, p=0.61). Rates of prescription of secondary prevention medication after initial clinic/hospital discharge were higher in clinic-referred than in hospital-referred patients for antiplatelets/anticoagulants (p<0.05) and lipid-lowering agents (p<0.001) and were maintained at 1-year follow-up. The mean (SD) secondary care cost was £8323 (13 133) for hospital-referred minor stroke versus £743 (1794) for clinic-referred cases. Conclusion Outpatient management of clinic-referred minor stroke is feasible and may be as safe as inpatient care. Rates of early hospital admission and recurrent stroke were low and uptake and maintenance of secondary prevention was high.

Response of Day-to-Day Home Blood Pressure Variability by Antihypertensive Drug Class After Transient Ischemic Attack or Nondisabling Stroke

Background and Purpose— Visit-to-visit variability in systolic blood pressure (SBP) is associated with an increased risk of stroke and was reduced in randomized trials by calcium channel blockers and diuretics but not by renin–angiotensin system inhibitors. However, time of day effects could not be determined. Day-to-day variability on home BP readings predicts stroke risk and potentially offers a practical method of monitoring response to variability-directed treatment. Methods— SBP mean, maximum, and variability (coefficient of variation=SD/mean) were determined in 500 consecutive transient ischemic attack or minor stroke patients on 1-month home BP monitoring (3 BPs, 3× daily). Hypertension was treated to a standard protocol. Differences in SBP variability from 3 to 10 days before to 8 to 15 days after starting or increasing calcium channel blockers/diuretics versus renin–angiotensin system inhibitors versus both were compared by general linear models, adjusted for risk factors and baseline BP. Results— Among 288 eligible interventions, variability in SBP was reduced after increased treatment with calcium channel blockers/diuretics versus both versus renin–angiotensin system inhibitors (−4.0 versus 6.9 versus 7.8%; P=0.015), primarily because of effects on maximum SBP (−4.6 versus −1.0 versus −1.0%; P=0.001), with no differences in effect on mean SBP. Class differences were greatest for early-morning SBP variability (3.6 versus 17.0 versus 38.3; P=0.002) and maximum (−4.8 versus −2.0 versus −0.7; P=0.001), with no effect on midmorning (P=0.29), evening (P=0.65), or diurnal variability (P=0.92). Conclusions— After transient ischemic attack or minor stroke, calcium channel blockers and diuretics reduced variability and maximum home SBP, primarily because of effects on morning readings. Home BP readings enable monitoring of response to SBP variability-directed treatment in patients with recent cerebrovascular events.

Low risk of rebound events after a short course of clopidogrel in acute TIA or minor stroke

Objective: The combination of aspirin and clopidogrel is indicated after acute coronary events and possibly for a short period after TIA or minor ischemic stroke. Early discontinuation of clopidogrel results in a transient rebound increase in risk of recurrence in acute coronary syndromes, but there are no published data on any similar rebound effect in patients with TIA or stroke that might inform the design of clinical trials of aspirin and clopidogrel in the acute phase. Methods: A 30-day course of aspirin and clopidogrel (both 75 mg daily) was given to high-risk patients with TIA or minor ischemic stroke seen acutely in the EXPRESS study clinic from April 1, 2002, to March 31, 2009. Clopidogrel was stopped after 30 days and aspirin continued. Recurrent events were ascertained at face-to-face follow-up. Results: A total of 320 patients were prescribed a 30-day course of aspirin and clopidogrel acutely after TIA or minor stroke. There were 5 recurrent ischemic strokes and 7 TIAs during the aspirin and clopidogrel treatment period, but no strokes and 4 TIAs during the 30 days after stopping clopidogrel. A similar temporal trend in stroke risk was seen in the 487 patients prescribed aspirin alone in the acute phase, with 12 and 5 strokes in the equivalent time periods. The upper 95% confidence intervals of the observed 0% risk of stroke during the 30 days after stopping clopidogrel was 1.15% overall. Conclusion: Although larger studies are required, our findings suggest there is unlikely to be a large rebound effect after discontinuation of a 30-day course of clopidogrel in acute TIA and minor ischemic stroke. However, planned trials of aspirin and clopidogrel in the acute phase after TIA or stroke should still follow-up beyond the cessation of clopidogrel treatment.

Population-Based Study of Disability and Institutionalization After Transient Ischemic Attack and Stroke

Background and Purpose— Long-term outcome information after transient ischemic attack (TIA) and stroke is required to help plan and allocate care services. We evaluated the impact of TIA and stroke on disability and institutionalization over 5 years using data from a population-based study. Methods— Patients from a UK population-based cohort study (Oxford Vascular Study) were recruited from 2002 to 2007 and followed up to 2012. Patients were followed up at 1, 6, 12, 24, and 60 months postevent and assessed using the modified Rankin scale. A multivariate regression analysis was performed to assess the predictors of disability postevent. Results— A total of 748 index stroke and 440 TIA cases were studied. For patients with TIA, disability levels increased from 14% (63 of 440) premorbidly to 23% (60 of 256) at 5 years (P=0.002), with occurrence of subsequent stroke being a major predictor of disability. For stroke survivors, the proportion disabled (modified Rankin scale >2) increased from 21% (154 of 748) premorbidly to 43% (273 of 634) at 1 month (P<0.001), with 39% (132 of 339) of survivors disabled 5 years after stroke. Five years postevent, 70% (483 of 690) of patients with stroke and 48% (179 of 375) of patients with TIA were either dead or disabled. The 5-year risk of care home institutionalization was 11% after TIA and 19% after stroke. The average 5-year cost per institutionalized patient was